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From OncoLog, September 2011, Vol. 56, No. 9

Novel Agents for Castrate-Resistant Prostate Cancer Include Potent Androgen Blockers and Immunotherapies

By Joe Munch

Figure: Bone scintiscans
Bone scintiscans taken before (left) and after 6 weeks of treatment with cabozantinib, a novel tyrosine kinase inhibitor, show a reduction in skeletal metastases in a patient with metastatic prostate cancer.

Despite progress in screening and therapy, prostate cancer continues to be a leading cause of cancer death among men worldwide.

When discovered in its early stages, prostate cancer can be effectively treated with surgery or radiation therapy; however, these therapies are not always curative. Current therapies for patients with recurrent or metastatic disease, which include surgical or medical castration, are initially effective in controlling the disease but are not curative.

Fortunately, a spate of novel therapies for castrate-resistant advanced prostate cancer have recently been approved by the U.S. Food and Drug Administration (FDA), and others are showing promise in clinical trials. Some of these therapies build upon an improved understanding of the disease process and the molecular pathways that drive it; others take advantage of the body’s inherent ability to fight cancer. All offer new hope to prostate cancer patients.

Standard hormone therapies

Treating patients in whom prostate cancer has spread or recurred typically involves suppressing the production of testosterone, the main driver of most prostate cancers, to curb or prevent tumor growth. In the past, this was accomplished with orchiectomy. Today, most patients are treated with nonsurgical hormone therapies (aka medical castration) that either lower testosterone production itself (e.g., luteinizing hormone–releasing hormone [LHRH] agonists such as leuprolide or LHRH antagonists such as degarelix) or block the effect of testosterone in cancer cells (e.g., bicalutamide). Such therapies are also being given with increasing frequency as neoadjuvant therapy for locally advanced disease to reduce the size of a prostate tumor prior to radiation therapy or prostatectomy with curative intent.

Hormone therapy can keep prostate cancer under control for years. But in many patients, it eventually fails. Such patients are said to have castrate-resistant prostate cancer—once called hormone-refractory or androgen-independent disease—which is defined as disease that persists despite therapies that lower serum testosterone to less than 50 ng/dL.

“Statistically, we know that most men, probably up to 90% of them, who initially present with androgen-dependent disease will initially respond to hormone therapy,” said Paul Corn, M.D., Ph.D., an assistant professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center. “However, if those men live long enough, a sizable proportion eventually develop castrate-resistant prostate cancer. And there’s extreme heterogeneity in how long a patient will benefit from hormone ablative therapy—it could be 6 months or 10 years.”

New hormone therapies

Fortunately, many cancers that become resistant or no longer responsive to therapies that block androgen signaling or reduce androgen levels can respond to other hormone therapies, according to Dr. Corn. “Even when patients have castrate levels of testosterone, their disease can stop responding to one hormone therapy but begin responding when another hormone therapy is started.”

For a time, it was unknown how these patients’ diseases could respond to additional therapies despite such low testosterone levels.

“When we measure testosterone levels in patients, we are measuring only serum testosterone, which is produced mostly by the testes and to a lesser extent in the adrenal glands. But a number of studies have demonstrated that one adaptation in advanced prostate cancers is that they make their own testosterone. They become like an endocrine organ,” Dr. Corn said. “Now we understand that it’s the paracrine or autocrine production of androgen within the tumor that is likely driving tumor growth, and this production is not revealed in serum levels.”

In response to this finding, researchers are developing novel ways to block or suppress androgen production and thus tumor growth and progression. For example, abiraterone, which the FDA approved earlier this year for the treatment of metastatic prostate cancer, blocks androgen production not only in the testes but also in the adrenal glands and the prostate tumor itself by preventing steroid reactions involving two critical enzymes in the testosterone synthesis pathway. Another agent, MDV3100, which interferes with testosterone’s ability to interact with prostate cancer cells, is showing promise in clinical trials.

“New therapies like abiraterone are extremely potent—probably several orders of magnitude more potent than the androgen-ablative therapies we had before now,” Dr. Corn said. “But the important thing is that they block all sources of testosterone synthesis.”

New chemotherapy options

Docetaxel-based chemotherapy is usually offered after hormone therapy options have been exhausted in patients who are found to have castrate-resistant prostate cancer. At MD Anderson, outside of clinical trials, chemotherapy is typically given to avoid or treat symptoms related to advanced disease, including bone pain or obstruction of urine flow.

“For patients who have symptoms associated with their cancer, chemotherapy can significantly improve their quality of life,” Dr. Corn said. “They might go from ‘I can’t even walk’ to ‘I’m out golfing.’”

If tumor cells develop resistance to a chemotherapy drug, however, its positive effects become short-lived. Fortunately, other chemotherapy drugs can be offered after docetaxel. For example, another taxane derivative, cabazitaxel, was shown to prolong life in patients who had already received docetaxel and was approved as a second-line therapy for patients with castrate-resistant metastatic prostate cancer in 2010. At MD Anderson, Dr. Corn and other researchers are in the process of testing whether combining cabazitaxel with other chemotherapy drugs will work better than cabazitaxel alone.

Photo: Drs. Padmanee Sharma and Paul Corn
Dr. Padmanee Sharma and Dr. Paul Corn both serve as principal investigators in clinical studies of new treatments for castrate-resistant prostate cancer.

Even if a patient’s tumor develops resistance to second-line chemotherapy, a different chemotherapy drug can be used. “We have experience with other third- and fourth-line chemotherapy combinations. We really try to keep going if at all possible and if the patient will benefit,” Dr. Corn said. “There are a number of drugs that have not necessarily been tested for efficacy in a randomized phase III study, but we certainly use them in a serial manner to try to prolong life and preserve quality of life.” Given the advances of the past 5 years, tumors that may have once been routinely treated with chemotherapy are now studied to determine whether they will respond to more potent blockers of androgen signaling before chemotherapy is necessary.

“We’re recognizing that we may be able to refine when we have to give chemotherapy by understanding the underlying biology of the tumor involved,” Dr. Corn said.

New tyrosine kinase inhibitors

A number of new drugs block growth-promoting pathways important in the progression of prostate cancer and the development of skeletal metastases. Examples of drugs in this category—tyrosine kinase inhibitors—include dasatinib, cabozantinib, and dovitinib. Studies of these three agents are under way at MD Anderson.

“These drugs work quite differently from androgen-ablative agents and chemotherapies,” Dr. Corn said. “We are still working out the exact mechanisms, but these drugs appear to interfere with the ability of prostate tumors to promote their own blood supply and remodel bone.”

New immunotherapy options

Advances against prostate cancer have also been made in therapies that utilize the body’s immune system to fight the disease. An improved understanding of T cell regulation and the tumor microenvironment in recent years has enabled researchers to design therapies that spur the body’s defense mechanisms to attack tumor cells.

“Immunotherapy for cancer has been explored for decades now, going all the way back to Coley’s toxins in the 1890s. But only recently have we been able to show that immunotherapy can provide a survival benefit for patients with prostate cancer in randomized phase III trials,” Padmanee Sharma, M.D., Ph.D., an associate professor in the Departments of Genitourinary Medical Oncology and Immunology, said.

One such agent, the sipuleucel-T (Provenge) vaccine, was approved for use in patients with advanced prostate cancer in 2010. Another agent, ipilimumab, an anti–cytotoxic T lymphocyte antigen (CTLA)-4 monoclonal antibody, has already been approved to treat melanoma and is now being investigated in patients with different stages of prostate cancer in several clinical trials at MD Anderson.

Therapeutic vaccine

Sipuleucel-T is an autologous cell–based immunotherapy. A patient’s white blood cells are harvested via leukophoresis and incubated with a fusion protein containing prostatic acid phosphatase (PAP), an antigen expressed on prostate cancer cells, and granulocyte-macrophage colony-stimulating factor, an immune-modulating cytokine. The treated cells are then reinjected into the patient. The belief is that sipuleucel-T enables T cells to recognize PAP, thereby allowing them to attack PAP-expressing tumor cells in the body.

The way in which sipuleucel-T extends survival is, however, not yet fully understood. According to Dr. Corn, the survival benefit that sipuleucel-T offers has not been accompanied by the usual benchmarks researchers use to determine the effectiveness of a cancer therapy.

“Most of the time, when a drug prolongs survival, it prevents progression of the disease. While sipuleucel-T prolongs disease-specific survival, it doesn’t prolong progression-free survival, which is somewhat counterintuitive,” Dr. Corn said. “And it doesn’t consistently make prostate-specific antigen levels go down, shrink lymph nodes, or make bone scans appear better.”

At MD Anderson, sipuleucel-T is typically given to patients with asymptomatic metastatic prostate cancer in whom androgen-ablative therapies are starting to fail but who have not yet received chemotherapy. In these patients, the disease is not rapidly progressing, and life expectancy is long enough to allow sipuleucel-T to work. Researchers are still trying to determine which patients will optimally benefit from sipuleucel-T.

Sipuleucel-T is an FDA-approved therapy option for patients with advanced prostate cancer, and other therapies available through clinical trials may be employed if sipuleucel-T fails.

“We never think of ‘last options,’” Dr. Sharma said.

Anti–CTLA-4 therapy

Unlike sipuleucel-T, which enables T cells to target prostate tumor cells specifically, ipilimumab enhances a general T cell response against all tumor cells.

In short, T cells are activated when the T cell receptor and the CD28 molecule on T cells are both engaged by their respective ligands, which sends an “on” signal. Shortly after T cells are activated, a series of signals within the cells leads to the expression of the “off ” switch, known as CTLA-4. CTLA-4 acts to limit T cell responses, which is necessary in normal settings to prevent damage to surrounding normal cells and tissues. But in the setting of bulky tumors, CTLA-4 may hinder the function of tumor-specific T cells.

“When you give ipilimumab, all you’re doing is blocking the ‘off’ switch; you’re allowing the ‘on’ switch to continue for a longer period of time,” Dr. Sharma said.

Because anti–CTLA-4 therapy enhances T cell responses against tumors, Dr. Sharma said, it is potentially applicable to many tumor types. Ongoing studies are investigating ipilimumab’s use in other cancer types including non–small cell lung cancer, breast cancer, and ovarian cancer.

Dr. Sharma and her colleagues are testing ipilimumab in patients with prostate cancer. In one study, patients with metastatic prostate cancer are given ipilimumab in addition to hormone therapy. Because hormone therapy enables tumor cell death, which in turn triggers an immune response, it is hypothesized that ipilimumab will enhance the immune response, possibly providing a greater benefit than hormone therapy alone.

In another study, patients whose prostate cancer has metastasized to the bone and for whom hormone therapy and chemotherapy have failed receive ipilimumab after radiation therapy is given to bony lesions. Ipilimumab is given to potentially increase the immune response initiated by the radiation-induced cell death and subsequent release of antigens.

In a third study, patients with localized prostate cancer who are being considered for prostatectomy but have a very high risk of recurrence (lymph node involvement, high Gleason score, and/or high grade of disease) receive ipilimumab in combination with leuprolide acetate to potentially boost the immune response to the tumor. These patients then undergo surgery.

Although ipilimumab can shut down CTLA-4 in everyone (because CTLA-4 is present in every human), it does not elicit an antitumor response in everyone.

“Why some patients have an anti-tumor response and others don’t is still a mystery,” Dr. Sharma said. “That’s why we’re investigating ipilimumab in patients with early-stage disease who will undergo prostate surgery. Obtaining some tissue specimens that we can study will help us understand the immune response that’s being generated.”

Toward that goal, researchers will continue to explore combinations of immunotherapies or combinations of immunotherapies and standard therapies.

“We think that the combination approach will allow the best clinical benefit,” Dr. Sharma said. “But what those combinations are and how to give them still need to be explored.”

For more information, contact Dr. Paul Corn at 713-563-7208 or Dr. Padmanee Sharma at 713-792-2830.

Other articles in OncoLog, September 2011 issue:


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